Preclinical experiments can inform the drug development

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The armamentarium of immune suppressive agents used in the treatment of autoimmune myasthenia gravis (MG) has largely emanated from the transplant literature and experience with the use of these drugs in the treatment of other autoimmune disorders (Sieb, 2014). At first glance, this may seem surprising given that most common antigenic targets of the autoimmune response in MG are well known and the availability of a well-studied animal models of MG either experimental autoimmune myasthenia gravis (EAMG) produced by immunization with the acetylcholine receptor (AChR) or muscle specific tyrosine kinase (MuSK) or passive transfer of autoantibody (PTMG) (Baggi et al., 2012 and Berrih-Aknin and Le Panse, 2014).

With the exception of the C5 complement inhibitor eculizumab (Howard et al., 2013), which was originally found to be effective in PTMG rat (Zhou et al., 2007), none of the therapies currently used for treatment of MG emerged from pre-clinical work in animal models. Upon closer inspection, however, it is clear that there are limitations to EAMG as a tool for pre-clinical assessment of potential therapeutic agents, and these issues will be discussed in greater detail elsewhere in this special issue. Here we focus on how experience from preclinical assessment in patients with MG might be used to enhance the utility of the EAMG rodent models for pre-clinical evaluation of therapeutics prior to their advancement into human preclinical trials.

The availability of several drugs that have proven efficacy in humans with MG may provide an opportunity to validate pre-clinical models for their predictive therapeutic value. This could be accomplished through an evaluation of existing drugs in pre-clinical models. A lack of efficacy of these drugs in a pre-clinical model would call into question the value of such models for evaluating novel therapeutics. By contrast, demonstrating that these drugs are effective in a pre-clinical model would lend support to the approach of using that model for testing new drugs.

Other issues to consider include the pharmacodynamic properties and toxicity of a therapeutic, which are likely to differ between rodents and humans. This in turn may make it appear that an agent lacks efficacy in a preclinical trial model because of rapid clearance, poor absorption, a large volume of distribution, or adverse effects. Further, immunosuppressive agents have time to efficacy of months to over a year. Given that rodents' lifespans differ profoundly from humans, efficacy evaluations may not be possible. Investigators need to consider these points in utilizing effective human therapeutics to validate pre-clinical models. Equally important, each of these differences between rodents and humans should be carefully considered in deciding whether an experimental therapeutic should be tested in rodents and the implications of the results—positive or negative—for translation into human studies.